The Roles of the L4-22K and L4-33K Proteins during Adenovirus Infection

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Abstract

Adenoviruses are a common cause of upper respiratory tract infection, conjunctivitis, and gastroenteritis. Fortunately, most of these infections are self-limiting and rarely cause severe or lethal diseases. Based on its characteristics of safety, easy manipulation and production, adenovirus has been widely used as a gene therapy vector in preclinical settings. Despite the intensive study of adenovirus in the past four decades, the mechanism for viral genome packaging is not fully understood. My dissertation focuses on two viral late gene products, L4-22K and L4-33K, to explore their functions during adenovirus infection, with an emphasis on their roles in viral genome packaging. By making specific mutant viruses that are deficient in making L4-22K or L4-33K proteins, I have found both proteins are absolutely required to make progeny viruses in infected human cells. Different approaches were used to pinpoint the roles that L4-22K and L4-33K play during the virus life cycle. For L4-22K, my work has shown it plays important roles in virus assembly, viral genome packaging and viral infection-induced cell lysis, which consist of the crucial final steps of adenovirus infection to produce and spread the progeny viruses. It does so by switching the mode of infection from the early to late phase to assemble progeny viruses, initiating the viral genome packaging process to finalize virus production, and facilitating cell lysis to spread the viruses. This work establishes the essential roles of L4-22K during adenovirus infection and provides insights for coordination of late events of adenovirus infection. For L4-33K, my results confirm its role as a virus-encoded alternative RNA splicing factor and identify its primary targets of regulation: proteins IIIa and pVI. Further analyses have shown that L4-33K regulates IIIa expression to package the viral genome into capsids, and may regulate adenovirus protease activity for virion maturation.